1. Field of Invention
This invention relates to disubstituted polycyclic compounds, to pharmaceutical compositions thereof, and methods of use in mammals to treat cognitive disorders, neurological dysfunction, and/or mood disturbances such as, but not limited to degenerative nervous system diseases. Additionally, these compounds can be used as reagents in studies on the biochemical mechanism of neurotransmitter based diseases.
2. Background Including Prior Art
Increasingly there is a need for effective treatments for nervous system disorders and neurological deficiencies. Many of these diseases correlate with increasing age due mainly to degenerative changes in the nervous systems. Although in early stages of some diseases, certain systems are rather specifically affected (e.g., cholinergic systems in Alzheimer's Disease and Myasthenia Gravis, the dopaminergic system in Parkinson's Disease, etc.), multiple neurotransmitter system deficiencies (acetylcholine, dopamine, norepinephrine, serotonin) are generally found at later stages of disease such as senile dementia, multi-infarct dementia, Huntington's Disease, mental retardation, etc. This explains the generally observed multiple symptomatology that includes cognitive, neurological, and effective/psychotic components (see Gottfries, Psychopharmacol., 1985, 86, 245). Deficits in the synthesis and release of acetylcholine in the brain are generally thought to be related to cognitive impairment (see Francis, et al., New England J. Med., 1985, 7, 313) whereas neurological deficits (e.g. Parkinsonian symptoms) and mood/mental changes may be related to impairment of dopaminergic and serotonergic systems, respectively. Other neurological deficits (e.g. Myasthenia Gravis) are related to cholinergic deficiencies in the peripheral nervous system.
Treatment strategies employed previously encompass vasoactive drugs like vincamine and pentoxifylline; metabolic enhancers like ergoloid mesylates, piracetam, and naftidrofuryl; neurotransmitter precursors like I-DOPA, choline, and 5-hydroxytryptamine; transmitter metabolizing enzyme inhibitors such as physostigmine; and neuropeptides like adrenocorticotropic hormone and vasopressin-related peptides. Except for I-DOPA treatment for Parkinson's Disease and cholinesterase inhibitor treatment for Myasthenia Gravis, these treatment strategies have generally failed to enhance the residual function of the affected systems by enhancing the stimulus-induced release of neurotransmitters. Theoretically, such an enhancement would improve the signal-to noise ratio during chemical transmission of information, thereby reducing deficits in processes related to cognition, neurological function, and mood regulation.
Cook, L., et al., Drug Development Research 19:301-314 (1990), Nickolson, V. J., et al., Drug Development Research 19:285-300 (1990), and DeNoble, V. J., et al., Pharmacology Biochemistry & Behavior, Vol. 36, pp. 957-961 (1990), all have shown by invitro testing that the drug DuP 996, 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one, is useful in the treatment of cognition dysfunction. Saletu, B., et al., Br. J. Clin. Pharmac. (1989), 28, 1-16, suggest that DuP 996 may exhibit indirect action or may have an active metabolite, and that three metabolites have been identified, a mono-N-oxide, a bis-oxide and a C-dealkylated alcohol. Chem. Abstracts 111(13):108875p suggest that the following structure is one of the above-named metabolites metabolite of DuP 996: ##STR2##
Neither reference presented chemical data to support their hypotheses.
European Patent Application 311,010, published Apr. 12, 1989, discloses that .alpha., .alpha.-disubstituted aromatics or heteroaromatics of the formula: ##STR3## or a salt thereof wherein X and Y are taken together to form a saturated or unsaturated carbocyclic or heterocyclic first ring and the shown carbon in said ring is .alpha. to at least one additional aromatic ring or heteroaromatic ring fused to the first ring;
one of Het.sup.1 or Het.sup.2 is 2, 3, or 4-pyridyl; or 2, 4, or 5-pyrimidinyl, and the other is selected from PA1 R.sup.1 and R.sup.2 independently are H or C.sub.1 C.sub.3 alkyl; PA1 --H and --H.sup.1 independently are 6-membered heterocyclic aromatic rings containing at least one nitrogen atom as a part of the ring optionally substituted with one substituent selected from the group C.sub.1 -C.sub.3 alkyl, halo, OR.sup.1 or NR.sup.1 R.sup.2, or an N-oxide or pharmaceutically suitable acid addition salt thereof. These references claim the necessity of heteroaryl groups for activity. Patent WO 91/01/306, Feb. 7, 1991 discloses oxindole derivatives of formula: ##STR6## useful for treating senile dementia, i.e. improving brain functions and activating and protecting brain metabolism. In the above formula, R.sup.1 represents hydrogen, halogen, lower alkyl, or lower alkoxy; R.sup.2 represents hydrogen or lower alkyl; R.sup.3 represents --CH.sub.2 --R.sup.5, wherein R.sup.5 represents alkyl which may be cyclic, benzodioxanyl, or phenyl which may be substituted with a plurality of halogen, lower alkyl, lower alkoxy, hydroxy, diethylamino, trifluoromethyl, nitrile, nitro, or benzyloxy; alternatively R.sup.2 and R.sup.3 may be combined together to form .dbd.CH--R.sup.5, wherein R.sup.5 is defined above; and R.sup.4 represents 1-propylbutyl, pyridyl, phenyl or substituted phenyl. This reference only discloses imides and does not suggest alkyl or aryl substituted amides. PA1 R.sup.1 is 4-,3-, or 2-pyridyl, pyrimidyl; pyrazinyl, 2-fluoro-4-pyridyl or 3-fluoro-4-pyridyl; PA1 R.sup.2 is alkyl of 1 to 10 carbons, cycloalkyl of 3 to 8 carbons, 2-,3-, or 4-pyridyl, Phe or Phe-W; PA1 Phe is a phenyl group; PA1 W is F, Cl, Br, R.sup.4, --OH, --OR.sup.4, --NO.sub.2, --NH.sub.2, --NHR.sup.4, --NR.sup.4 R.sup.4, --CN, --S(O).sub.m --R.sup.4 ; PA1 R.sup.3 is H, F, Cl, Br,--CN,--OH,--NO.sub.2, --NH.sub.2,--CF.sub.3, --NHR.sup.4, --NR.sup.4 R.sup.4, R.sup.4, --OR.sup.4, --S(O).sub.m --R.sup.4 ; PA1 R.sup.4 and R.sup.4' are alkyl of 1 to 4 carbons, CH.sub.2 Phe--W or Phe--W; PA1 R.sup.5 is --(CH.sub.2).sub.n --Y or --OCOR.sup.4 ; PA1 Y is H, OH, NH.sub.2, --NHR.sup.4, --NR.sup.4 R.sup.4, --NHCOR.sup.4, --NHCO.sub.2 R.sup.4, F, Cl, Br, OR.sup.4, --S(O).sub.m R.sup.4, --CO.sub.2 H, --CO.sub.2 R.sup.4, --CN, --CONR.sup.4 R.sup.4, --CONHR.sup.4, --CONH.sub.2, --COR.sup.4 ; --CH.dbd.CHCO.sub.2 R.sup.4, OCOR.sup.4, Phe, Phe-W, -C.tbd.CCO.sub.2 R.sup.4, --CH.dbd.CHR.sup.4, or --C.tbd.CR.sup.4 ; PA1 m is 0, 1 or 2; PA1 n is 1 to 7; PA1 provided that, when Q is oxindole and R.sup.5 is (CH.sub.2).sub.n Y, then Y is other than OH; PA1 A and B together form .dbd.O; PA1 R.sup.1 is (a)4-pyridyl, (b)4-pyrimidyl, or (c) 2-fluoro-4-pyridyl; PA1 R.sup.5 is --(CH.sub.2).sub.n --Y; PA1 n is 1 to 5; PA1 Y is H, --OH, NH.sub.2, NHR.sup.4, NR.sup.4 R.sup.4, F, Cl, Br, --CO.sub.2 H, --CO.sub.2 R.sup.4, --CN, --CONHR.sup.4, --CONH.sub.2, --CONR.sup.4 R.sup.4, --COR.sup.4, --.dbd.CHCO.sub.2 R.sup.4, --OCOR.sup.4, or -Phe-W PA1 W is F, Cl, or Br; R.sup.4, --OR.sup.4, --S(O).sub.m --R.sup.4, --CN, --NO.sub.2, or --NH.sub.2 ; PA1 R.sup.4 is alkyl of 1 to 4 carbons, and m is 0, 1,2. PA1 R.sup.1 is (a)4-pyridyl, (b) 4-pyrimidyl, or (c) 2- fluoro-4-pyridyl; PA1 R.sup.5 is --(CH.sub.2).sub.n --Y; PA1 n is 1 to 4; PA1 Y is --CO.sub.2 R.sup.4, --CN, --CONHR.sup.4, --CH.dbd.CHCO.sub.2 R.sup.4, --OCOR.sup.4, PA1 R.sup.2 is 4-pyridyl, Phe or Phe-W, PA1 W is F, Cl, or Br; NO.sub.2, CN, or CH.sub.3 ; PA1 R.sup.3 is H, F, Cl, or Br; and PA1 R.sup.4 is alkyl of 1 to 2 carbons.
(a) 2, 3, or 4-pyridyl PA2 (b) 2, 4, or 5-pyrimidinyl PA2 (c) 2-pyrazinyl PA2 (d) 3 or 4-pyridazinyl, PA2 (e) 3 or 4-pyrazolyl, PA2 (f) 2 or 3-tetrahydrofuranyl, and PA2 (g) 3-thienyl
are useful as cognition enhancers. U.S. Pat. No. 4,760,083, issued to Myers et al. on Jul. 26, 1988, discloses that indolines of the following formula are useful for treatment of cognitive deficiencies: ##STR4## wherein p is 0 or 1; Z is 0 or S; R is C, --C.sub.10 alkyl, C.sub.1 -C.sub.3 cycloalkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or ##STR5## V, W, X and Y are independently halo, C, --C.sub.3 alkyl, OR.sup.1, NO.sub.2, CF.sub.3, CN or NR.sup.2 R.sup.2 ;
EP415-102-A discloses a series of 1,3-dihydro-1-(pyridinylamino)-2H-indol-2-ones as having analgesic, anticonvulsant, and/or memory enhancing activity and are useful in the treatment of Alzheimer's disease. ##STR7## where R.sup.1, R.sup.2 and R.sup.3 are independently hydrogen, loweralkyl, aryl, arylloweralkyl or heteroarylloweralkyl selected from the group consisting of pyridinylmethyl, pyridinylethyl, thienylmethyl, thienylethyl; or R.sup.2 and R.sup.3 together form a cycloalkane ring of 4 to 6 carbons or a spiro-fused aryl cycloalkane or heterocycloalkyl selected from the group consisting of piperidine and tetrahydropyran; X and Y are independently hydrogen, halogen, hydroxy, loweralkyl, loweralkoxy, nitro, amino or trifluoromethyl; m and n are independently integers of 1 to 3. This reference disclosed hydrazides and does not suggest alkyl or aryl substituted amides.